The drugs, agonists at the 5HT-2B serotonin receptor, were pulled from the market in 1997 following reports of heart valve problems.

Echocardiography in 5,743 former users of the drugs showed evidence of cardiac valvulopathy up to seven years later, reported Paul N. Hopkins, M.D., of the University of Utah, and colleagues online in BioMed Central Medicine.

Aortic or mitral regurgitation was detected in 19.6% of women and 11.8% of men in the study, conducted in a single clinic in Provo, Utah, from 1997 to 2004.

With a mean of 30.3 months of follow-up, aortic regurgitation worsened in 15.2% of participants initially diagnosed with it and the condition remained the same in 63.1%.

Similarly, mitral regurgitation was worse in 24.8% of patients and the same in 47.4%.

Patients examined earlier in the study -- that is, relatively soon after stopping fenfluramine treatment -- were more likely to show improvement in follow-up exams.

Duration of fenfluramine use was also strongly predictive of aortic, mitral, and tricuspid regurgitation, Dr. Hopkins and colleagues found.

For example, among participants whose exposure to fenfluramines lasted three to six months, the prevalence of moderate or severe aortic regurgitation was 3.6%, compared with 7.3% among those with exposures of a year or more (P<0.0001 for trend).

The researchers also found that valve surgeries were performed in 38 patients, including 25 with definite or probable fenfluramine-related pathology -- 0.44% across the entire cohort.

That is about seven times higher than would be expected in the general population, the researchers said.

They also determined that the presence of pulmonary hypertension was associated with mitral but not aortic regurgitation.

The researchers calculated odds ratios of 7.6, 15, and 28 that participants would have pulmonary hypertension if they had mild, moderate, or severe mitral regurgitation, respectively.

Participants' age was also a significant predictor of aortic and mitral regurgitation, the researchers said. Participants in their 60s or older were approximately three to four times more likely to have moderate or severe valvulopathy than those in their 20s and 30s.

Dr. Hopkins and colleagues said their study was the largest ever to examine duration of exposure to fenfluramines and the first to quantify the rate of valvular surgery related to past fenfluramine treatment.

They estimated that their cohort comprised half of all fenfluramine users in their geographic area. Patients were referred to the clinic in fulfillment of the FDA's recommendation that users of the drug be screened for possible heart valve damage.

"Our findings bring considerable harmony and closure to the issue of fenfluramine-induced valvulopathy," they wrote.

"Our finding of a strong effect of timing of the scan (in relation to stopping the medication) lends credibility to the high prevalence of early reports and is also in harmony with the lower, stable rates seen in later studies," the researchers said. "We found evidence for early improvement followed by relative stabilization."

They added that clinicians could expect to see fenfluramine-related valvulopathies requiring surgery "well into the future."

The study had no external funding.

Several authors reported having served as expert witnesses for plaintiffs in litigation, now concluded, related to fenfluramines. No other potential conflicts were disclosed.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine